This application describes an invention for detecting nuclear magnetic resonance using a mechanical oscillator. Three apparatuses are described which embody the invention. The first apparatus is designed to detect magnetic resonance in samples whose mass is of order one microgram. The second and third apparatuses are designed to detect magnetic resonance in samples whose size is that of individual molecules or atoms.
The invention described herein can be used to determine the structure of biological molecules, and in fact was devised with this objective in mind.
As a historical precedent, systems and methods for inductive detection of nuclear magnetic resonance found widespread medical application in imaging the human body. Similarly, the systems and methods for oscillator-based detection of nuclear magnetic resonance described herein have applications in imaging the structure of individual molecules, although the applications of oscillator-based detection are not necessarily confined to this area.
In understanding the utility of this invention, it is useful to enquire whether the inductive methods presently used in medical imaging might be adapted for use in imaging individual atoms and molecules. A hypothetical atomic-scale inductive imaging apparatus might employ transmitting and receiving antennas of a few nanometers in length, so that the sensitive volume would be of the same size as a typical protein molecule. Such an apparatus would effectively be a scaled-down version of a conventional medical imaging apparatus. The hypothetical transmitting and receiving antennas would monitor spin flips in the molecule by inductively coupling the spins to a sensitive electronic amplifier, just as they do in conventional imaging apparatuses.
A major difficulty with inductive imaging of molecules is that it is not clear how nanometer-scale transmitter or receiver coils could be fabricated, nor whether they would generate electric signals of detectable power. While it cannot be definitely asserted that inductive detection of magnetic resonance in a single nucleus is impractical or impossible, no practical molecular imaging apparatus using inductive detection methods has yet been demonstrated.
Thus there is a substantial need for a method for detecting magnetic resonance is molecule-sized samples.
The information that a molecular imaging apparatus could provide would be of substantial medical interest. Amino acid sequences are known for thousands of biologically important molecules, but the scientific community does not known the shapes of these molecules or how they work, except for a few exceptional cases.
This makes the rational design of treatments for (e.g.) AIDS very difficult. Of the proteins encoded by the AIDS genome, only one, namely HIV protease, has a known three-dimensional structure [1]. The remaining proteins, in particular the HIV reverse transcriptase molecule which is essential for retroviral replication, have so far proven resistant to x-ray crystallography, which is (at present) the most widely-used technique for determining protein structures. The missing structural information is a significant obstacle to the rational design of drugs and vaccines for AIDS.
As another example, cystic fibrosis is an inherited disorder associated with a defective gene which codes for the protein known as cystic fibrosis transmembrane conductance regulator (CFTR). Approximately one person in thirty carries a defective gene for CFTR. If both spouses carry the gene, then one in four of their children will be at severe risk for early death from pulmonary insufficiency and/or infection. Like the overwhelming majority of transmembrane proteins, CFTR is resistant to crystallization, and thus its structure cannot be determined by x-ray crystallography. Another obstacle is that CFTR is a large molecule, containing 1480 amino acids, and is too complex for conventional magnetic resonance spectra to give much structural information.
For these reasons the shape of the CFTR molecule is not known, not is it certain wheat the function of the normal protein is, nor is it known what structural defects are created by the known mutations associated with cystic fibrosis. This lack of information is a significant barrier to the development of methods for treating cystic fibrosis. Many other examples could be cited in which lack of information regarding molecular structure is a substantial obstacle to developing effective medical treatments.
This application describes a method and a system for detecting magnetic resonance which does not make use of inductive loops, but instead used mechanical oscillators to detect magnetic resonance, and which thereby avoids the practical difficulties associated with inductive detection of magnetic resonance in small samples.